We are studying the regulation and structure of the genes which code for fibrinogen, the major blood coagulation protein. We have found that fibrinogen mRNA levels are controlled through a complex feedback-like regulation involving the plasmin degradation products of fibrinogen and interleukin I. This same mechanism also appears to account for the induction of the acute phase reaction in response to injury or inflammation. This regulatory influence somehow coordinates the levels of each of the three fibrinogen mRNAs so that the genes are activated at the same time and to the same extent. We have begun studying the mechanisms underlying this coordinate regulation and have obtained cDNA and genomic clones for each of the three fibrinogen chains in the rat and human. Thus far, we have found that the three fibrinogen genes are linked on human chromosome four, that the activation of the three genes occurs by increasing the rate of transcription of mRNA from each of the three genes, and that homologous sequences exist at the 5' ends of the genes which might account for this regulation. We have also begun studying the hereditary human afibrinogenemias as models of defective fibrinogen production. Patients with these diseases do not make circulating fibrinogen. We have found that by examining the DNA using Southern blotting from patients with afibrinogenemias, that at least two genotypes underlie these diseases. The goals of our research are to understand the factors controlling and coordinating the expression of families of genes during differentiation and development.